The objective of this proposal is to develop further a system of clinical genetics that is faithful to biology, accurate, and, so far as possible, simple and practical. It comprises three sections. (1) The fate (dynamics) of a mutant trait, which bears on responsible decision-making and preventive clinical genetics. Six projects are proposed. Three of them are theoretical: to develop and enhance the theory of estimating evolutionary fitness (probability of permanant survival); the impact of a stochastic constraint on total populaton size; and the altriusm model (survival of a type through a collateral relative). The other three are applied: substantive studies in various diseases (achondroplasia, Marfan syndrome, Huntington Chorea, hyperlipoproteinemia); study of the impact of age and other factors on penetrance; and empirical studies on the relationship between infant mortality and evolutionary fitness. (2) Studies on various features related to genetic counseling: age-dependent penetrance, notably in hereditary polyposis coli; efficient use of information for consanguineous matings, including studies on bias in the estimation of the frequency of rare genes and the development of a coherent theory of ascertainment bias; segregation analysis in cartilage hair hypoplasia in the Amish; and development and application of the two-locus model (epistasis and parastasis) to congenital heart disease. (3) Studies on the mathematical modeling of diseases with special reference to carcinogenesis with age-depend manifestation and atherosclerosis.